Biotinidase deficiency

Untreated profound biotinidase deficiency usually becomes symptomatic between one week and ten years of age, most often in infancy. The principal neurological features are seizures and hypotonia; ataxia and developmental delay are seen in older affected individuals. Sensorineural hearing loss may occur in untreated symptomatic individuals and is often irreversible despite biotin therapy.

Cutaneous manifestations include skin rash, alopecia and recurrent viral or fungal infections related to immunological dysfunction; these features typically resolve with treatment. A subset of individuals remain asymptomatic until adolescence or adulthood, when they may develop sudden vision loss with progressive optic neuropathy, peripheral neuropathy and spastic paraparesis. Clinical expressivity is highly variable within and between families. Individuals identified before symptom onset, typically through newborn screening, who receive biotin from infancy usually do not develop the clinical features of the disorder.

Lifelong oral biotin supplementation is highly effective and can prevent the development of symptoms when initiated before clinical onset. Neurological complications such as hearing loss, optic atrophy and developmental delay may be only partially reversible once established.

The estimated incidence of profound and partial biotinidase deficiency combined is about 1 in 61,000 live births. Frequencies are higher in populations with high rates of consanguinity, and partial deficiency predominates in some screening programmes.

Biotinidase deficiency is caused by biallelic germline pathogenic variants in BTD (3p25.1). BTD encodes biotinidase, the enzyme that releases free biotin from biocytin and biotinyl-peptides during normal protein turnover, thereby recycling this water-soluble cofactor for the biotin-dependent carboxylases. Loss of biotinidase activity depletes available biotin and causes secondary multiple carboxylase deficiency, disrupting amino acid, fatty acid and carbohydrate metabolism. The disease mechanism is loss of function. Partial deficiency is commonly associated with the D444H variant in combination with a profound-deficiency variant on the other allele.

Biotinidase deficiency is inherited in an autosomal recessive manner. The parents of an affected child are obligate carriers, each transmitting one pathogenic BTD variant. Each pregnancy of carrier parents carries a 25% recurrence risk. Carrier testing of at-risk relatives requires prior identification of the familial pathogenic variants. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis rests on demonstration of deficient serum biotinidase activity: less than 10% of mean normal activity in profound deficiency and 10% to 30% in partial deficiency. Newborn screening uses fluorometric or colorimetric assays on dried blood spots, with confirmatory quantitative measurement in serum. Supportive biochemical findings include ketolactic acidaemia, organic aciduria (raised 3-hydroxyisovalerate and related metabolites) and mild hyperammonaemia.

Main differential diagnoses include:

• Holocarboxylase synthetase deficiency: similar multiple carboxylase deficiency but with normal serum biotinidase activity and onset before three months; HLCS
• Isolated 3-methylcrotonyl-CoA carboxylase deficiency: raised 3-methylcrotonic acid, 3-methylcrotonylglycine and 3-hydroxyisovaleric acid; MCCC1, MCCC2
• : seizures, hypotonia, acidosis and hyperammonaemia with raised 3-hydroxypropionic and methylcitric acid; PCCA, PCCB

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic BTD variants, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive and carrier testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

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